EP1351676B1 - Use of isovaleryl l-carnitine for the preparation of a medicament for the prevention and cure of osteoporosis - Google Patents

Use of isovaleryl l-carnitine for the preparation of a medicament for the prevention and cure of osteoporosis Download PDF

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Publication number
EP1351676B1
EP1351676B1 EP01271219A EP01271219A EP1351676B1 EP 1351676 B1 EP1351676 B1 EP 1351676B1 EP 01271219 A EP01271219 A EP 01271219A EP 01271219 A EP01271219 A EP 01271219A EP 1351676 B1 EP1351676 B1 EP 1351676B1
Authority
EP
European Patent Office
Prior art keywords
carnitine
acid
isovaleryl
fumarate
osteoporosis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP01271219A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1351676A1 (en
Inventor
Aleardo Sigma-Tau Ind. Farm.Riunite Spa Koverech
Alberta Zallone
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sigma Tau Industrie Farmaceutiche Riunite SpA
Original Assignee
Sigma Tau Industrie Farmaceutiche Riunite SpA
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Filing date
Publication date
Application filed by Sigma Tau Industrie Farmaceutiche Riunite SpA filed Critical Sigma Tau Industrie Farmaceutiche Riunite SpA
Publication of EP1351676A1 publication Critical patent/EP1351676A1/en
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Publication of EP1351676B1 publication Critical patent/EP1351676B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to the use of isovaleryl L-carnitine for the preparation of a medicament for the prevention and cure of fractures.
  • the hospitalisation period of patients with bone fractures which may last some day or some months, depends from the type of fracture, the age, and from the general conditions of the patients.
  • the convalescence period depends on the gravity of the pathology. At the end of this period patients come back to the hospital for the radiographic controls of the bony callus formation.
  • WO 98/46233 describes a pharmaceutical compositions comprising an alkanoyl L-carnitine in combination with the dehydroepiandrosterone (DHEA) or the dehydroepiandrosterone sulphate (DHEA-S) capable to stimulate the multiplication and growth of the osteoblast.
  • DHEA dehydroepiandrosterone
  • DHEA-S dehydroepiandrosterone sulphate
  • WO 99/66913 describes compositions useful for the treatment of the osteoporosis and menopausal syndromes which comprise propionyl L-carnitine in combination with 4'-5,7-trihydroxiflavone.
  • the patent FR 2765804 describes compositions useful for the treatment of osteoporosis containing calcium pidolate, calcium carbonate, and carnitine.
  • WO 98/01128 describes the use of acetyl L-carnitine, isovaleryl L-carnitine and propionyl L-carnitine for increasing the IGF-1 levels for the treatment and prevention of cytological disorders and pathologies related to IGF 1.
  • WO 95/05168 describes an oral medicament at controlled release comprising carnitine, which does not causes gastrointestinal irritation, for the treatment of the osteoporosis.
  • mice treated with L-carnitine increase the production of osteocalcine (index of better calcification), while in the same animals the treatment with acetyl L-carnitine reduces the production of this marker during the formation of the bone matrix.
  • isovaleryl L-carnitine promotes the formation and proliferation of osteoblasts and is a therapeutic agent useful for the prevention and treatment of fractures during post-menopausal osteoporosis or secondary to elderly.
  • isovaleryl L-carnitine shows to be more active than L-carnitine, or as active as, but a doses less than 10 or 20 times, respect to L-carnitine.
  • Is therefore object of the present invention the use of isovaleryl L-carnitine or a pharmacological acceptable salt thereof, for preparing a medicament useful for increasing the healing of fractures.
  • Non-limiting examples of suitable salts include the chloride, bromide, orotate, acid aspartate, acid citrate, magnesium citrate, acid phosphate, fumarate, acid fumarate, magnesium fumarate, lactate, maleate, acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulphate, glucose phosphate, tartrate, acid tartrate, magnesium tartrate, 2-amino etanesulfonate, magnesium 2-amino etanesulfonate, coline tartrate and trichloroacetate.
  • the compound according to the present invention can be administered to patients in need, either alone or in concomitance with vitamins, mineral salts and/or other known drugs useful for the treatment of fractures during osteoporosis.
  • the differentiated human osteoblasts were prepared starting from bone fragments obtained during surgical operation following the procedure described in Calcif. Tissue Int. 62: 362-365, 1998; and in Calcif. Tissue Int. 37: 453-460, 1985.
  • bone fragments were undertaken to enzymatic digestion with collagenase (1 mg/ml) diluted in phosphate buffer in order to remove fibroblasts, haematic endothelial cells or bone marrow cells, if any.
  • the fragments so cleaned were maintained in culture in presence of a medium containing 20% of foetal calf serum (FCS) to obtain osteoblasts population for explant.
  • FCS foetal calf serum
  • the cells so obtained were characterised to verify their osteoblastic phenotype then used for the experiments.
  • the cellular proliferation test was done growing the cells in 96 well plates, in medium without FCS, and with bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the cells were exposed to increasing doses of L-carnitine fumarate and isovaleryl L-carnitine fumarate.
  • the positive control group was constituted by cells growing in presence of FCS (15%).
  • the collagen production represents a method for the evaluation of the osteoblast activity.
  • isovaleryl L-carnitine shows to be more active in some experiments, and as active as, at doses at least 10 times lower, also respect to the reference compound (L-carnitine).
  • the amount of the drug to be administered to patients in need will be decided by the physician on the base of the age, weight and general conditions of the patient.
  • the unitary dosage to be administered will be about 0,5-3 g/day, preferably 1-2 g/ day, in solid form, powder, granular or liposomic in pills, capsules, granulates, powder, vials for oral, parenteral, rectal or topic use.
  • These administration forms may further contain vitamins, mineral salts, useful for the treatment of fractures during osteoporosis.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
EP01271219A 2000-12-21 2001-12-04 Use of isovaleryl l-carnitine for the preparation of a medicament for the prevention and cure of osteoporosis Expired - Lifetime EP1351676B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITRM20000688 2000-12-21
IT2000RM000688A IT1317079B1 (it) 2000-12-21 2000-12-21 Uso della isovaleril l-carnitina per la preparazione di un medicamentoper la prevenzione e cura dell'osteoporosi.
PCT/IT2001/000614 WO2002049639A1 (en) 2000-12-21 2001-12-04 Use of isovaleryl l-carnitine for the preparation of a medicament for the prevention and cure of osteoporosis

Publications (2)

Publication Number Publication Date
EP1351676A1 EP1351676A1 (en) 2003-10-15
EP1351676B1 true EP1351676B1 (en) 2005-08-17

Family

ID=11455074

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01271219A Expired - Lifetime EP1351676B1 (en) 2000-12-21 2001-12-04 Use of isovaleryl l-carnitine for the preparation of a medicament for the prevention and cure of osteoporosis

Country Status (15)

Country Link
US (2) US6906102B2 (sk)
EP (1) EP1351676B1 (sk)
AT (1) ATE301998T1 (sk)
AU (1) AU2002217431A1 (sk)
CA (1) CA2434962C (sk)
CZ (1) CZ304356B6 (sk)
DE (1) DE60112802T2 (sk)
DK (1) DK1351676T3 (sk)
ES (1) ES2247005T3 (sk)
HU (1) HU227342B1 (sk)
IT (1) IT1317079B1 (sk)
MX (1) MXPA03006332A (sk)
PL (1) PL207879B1 (sk)
SK (1) SK287306B6 (sk)
WO (1) WO2002049639A1 (sk)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1290801B1 (it) * 1996-07-05 1998-12-11 Mendes Srl Uso della acetil l-carnitina, della isovaleril l-carnitina, della propionil l-carnitina o dei loro sali farmacologicamente accettabili
IT1291141B1 (it) * 1997-04-16 1998-12-29 Sigma Tau Ind Farmaceuti Composizione farmaceutica comprendente una alcanoil l-carnitina, atta a stimolare la moltiplicazione e la crescita degli osteoblasti
IT1299191B1 (it) 1998-06-23 2000-02-29 Sigma Tau Healthscience Spa Composizione atta a prevenire e trattare l'osteoporosi e le alterazioni legate alla menopausa

Also Published As

Publication number Publication date
DE60112802D1 (de) 2005-09-22
HUP0400735A3 (en) 2009-01-28
US20050143458A1 (en) 2005-06-30
CZ20031890A3 (cs) 2004-04-14
US7084174B2 (en) 2006-08-01
ES2247005T3 (es) 2006-03-01
HUP0400735A2 (hu) 2004-07-28
ITRM20000688A1 (it) 2002-06-21
WO2002049639A1 (en) 2002-06-27
CA2434962C (en) 2010-02-09
SK287306B6 (sk) 2010-06-07
DK1351676T3 (da) 2005-12-19
PL367293A1 (en) 2005-02-21
ATE301998T1 (de) 2005-09-15
IT1317079B1 (it) 2003-05-26
SK8912003A3 (en) 2003-11-04
PL207879B1 (pl) 2011-02-28
EP1351676A1 (en) 2003-10-15
MXPA03006332A (es) 2004-04-21
AU2002217431A1 (en) 2002-07-01
ITRM20000688A0 (it) 2000-12-21
CA2434962A1 (en) 2002-06-27
CZ304356B6 (cs) 2014-03-26
US6906102B2 (en) 2005-06-14
DE60112802T2 (de) 2006-03-16
US20040077718A1 (en) 2004-04-22
HU227342B1 (en) 2011-04-28

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